NIH Public Access: Etiology and Treatment of Hypogonadism in Adolescents

NIH Public Access
Author Manuscript
Pediatr Clin North Am. Author manuscript; available in PMC 2014 July 17.
Published in final edited form as:
NIH-PA Author Manuscript
Pediatr Clin North Am. 2011 October ; 58(5): 1181–x. doi:10.1016/j.pcl.2011.07.009.
Etiology and Treatment of Hypogonadism in Adolescents

Vidhya Viswanathan, MD* and Erica A. Eugster, MD
Section of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana
University School of Medicine, Room 5960, 702 Barnhill Drive, Indianapolis, IN 46202, USA
Keywords
Hypergonadotropic hypogonadism; Hypogonadotropic hypogonadism; Adolescents; Delayed
puberty; Treatment
Factors that mitigate the onset of puberty have yet to be fully elucidated. Gonadarche refers
to the onset of gonadal sex steroid production during puberty. Gonadarche results from
pulsatile gonadotropin releasing hormone (GnRH) secretion from the hypothalamus. GnRH
secretion occurs every 60 to 90 minutes,1 and there is subsequent release of the pituitary
gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) initially
during sleep,2 which leads to gonadal stimulation. LH stimulates Leydig cell hyperplasia in
males and subsequent testosterone release. FSH has little effect in males until the onset of
spermarche (sperm maturation). In females, FSH stimulates the production of estradiol via
ovarian follicular development. Testosterone and estradiol secretion lead to the development
of secondary sexual characteristics. Adequate functioning at all levels of the hypothalamic-
pituitary-gonadal axis is necessary for normal gonadal development and subsequent sex
steroid production. Deficiencies at any level of the axis can lead to a hypogonadal state.
In boys, hypogonadism can manifest as a complete lack of secondary sexual development or

failure of normal pubertal progression. In girls, it can present with failure of pubertal
initiation, failure of pubertal progression, or menstrual irregularities. Abnormalities within
the hypothalamus or pituitary lead to hypogonadotropic hypogonadism whereas primary
gonadal failure is characterized as hypergonadotropic hypogonadism.
HYPOGONADOTROPIC HYPOGONADISM
Hypogonadotropic hypogonadism can be attributed to a variety of congenital origins
including single gene mutations, idiopathic forms, and genetic syndromes. Acquired causes
of hypogonadotropic hypogonadism include central nervous system (CNS) insults such as
trauma, irradiation, and intracranial tumors. By far the most common cause of
hypogonadotropic hypogonadism is transient, and is termed constitutional delay of growth
and puberty (CDGP). Each of these causes is briefly discussed here, and the molecular
genetic causes of hypogonadotropic hypogonadism are shown in Table 1.
© 2011 Elsevier Inc. All rights reserved.

*
Corresponding author. vviswana@iupui.edu.
Viswanathan and Eugster Page 2
Constitutional Delay of Growth and Puberty

CDGP is a variation of normal development that can be difficult to differentiate from
pathologic hypogonadotropic hypogonadism. In this condition, puberty and the pubertal

growth spurt occur at or later than the extreme upper end of the normal age. The diagnosis is
made more often in boys than girls, likely due to referral bias, and has a strongly familial
pattern.3 Skeletal maturation is delayed in comparison with chronologic age. CDGP results
in delayed but normal puberty; thus puberty progresses through the normal stages but starts
at a later time. Children with CDGP achieve their genetic potential for height,4 and
laboratory evaluation is normal. Some patients benefit from short-term treatment to augment
secondary sexual development and boost linear growth.5
Congenital Origins
Gene defects
Nuclear receptor mutations: Nuclear receptors influence gene transcription at multiple
levels, and exert their effects in a time- and dosage-specific fashion. An important nuclear
receptor involved in gonadotropin secretion is steroidogenic factor-1 (SF-1), a key regulator
of genes involved in sexual differentiation, steroidogenesis, and reproduction. SF-1
knockout mice show marked abnormalities in the development of the hypothalamus and
impaired development of pituitary gonadotropes, with decreased levels of serum
gonadotropins as well as gonadal dysgenesis.6 Target genes of SF-1 within the
hypothalamus and pituitary include the gonadotropin releasing hormone receptor (GnRHR)
and the β subunit of LH. Both heterozygous and homozygous mutations in the DNA binding
domain of SF-1 result in complete XY sex reversal, testicular dysgenesis, and adrenal failure
in genotypic males. A milder phenotype has also been described in which there is impaired
gonadal but intact adrenal function.7 In a genetic female, a heterozygous SF-1 mutation has
been associated with primary adrenal failure but normal ovarian development.8 Thus, SF-1
mutations exist within a broad clinical spectrum that will undoubtedly continue to expand.
DAX-1 is an orphan nuclear receptor that is involved in steroidogenesis and functions as a

repressor of SF-1 mediated transcription. Mutations have been identified in NROB1, the
gene that encodes DAX1, on the Xp21 locus. Males with DAX1 mutations typically present
with early-onset adrenal insufficiency and subsequent delayed puberty secondary to
hypogonadotropic hypogonadism.9 However, a delayed presentation of primary adrenal
insufficiency has also been reported.10 DAX1 mutations can lead to both hypothalamic and
pituitary dysfunction with decreased GnRH and gonadotropin secretion.11 DAX1 mutations
can also cause defects in spermatogenesis, and in one study affected males also had evidence
of azospermia.12 Therefore, mutations in DAX-1, as in SF-1, can lead to the development of
hypogonadism in a multitude of ways.
Kallman syndrome: Impairment of GnRH secretion can also occur from defects in
migration of GnRH producing neurons. Kallman syndrome (KS) refers to the combination
of hypogonadotropic hypogonadism and anosmia. The X-linked form results from a defect
in the migration of GnRH and olfactory neurons due to a mutation in the KAL1 gene. This
gene encodes for anosmin-1, a glycoprotein essential for neuronal migration and growth.13
Individuals with KS also have aplasia of the olfactory bulb as noted on magnetic resonance
imaging (MRI).14 Although KAL1 gene defects have been the prototype of KS, there is
emerging evidence that autosomal forms may be more prevalent than previously thought. In
one study, KAL1 gene defects accounted for only 14% of cases with familial KS. Mutations
in unidentified autosomal genes were postulated to cause the remainder. Subjects with
presumed autosomal gene defects had some response to GnRH pulses, indicating partial
preservation of hypothalamic GnRH-secreting neurons, though still with phenotypic
similarity to the X-linked version of the syndrome.15 Fibroblast growth receptor 1 (FGFR1)
mutations may account for as many as 10% of cases,16 and mutations in the prokineticin 2
(PROK2) gene have also been identified in individuals with KS and normosmic
hypogonadotropic hypogo-nadism.17 No matter what the underlying molecular genetic
cause, lack of adequate GnRH secretion leads to decreased circulating gonadotropins in both
autosomal and X-linked cases.
Isolated hypogonadotropic hypogonadism: Isolated hypogonadotropic hypogonadism

(IHH) refers to cases in which anosmia is absent. One potential cause is loss of function
mutations of the GnRHR, a G-protein coupled receptor. At least 8 mutations of the GnRHR
in 7 families have been identified. Notable genotype-phenotype variation exists even within
members of the same kindred due to incomplete activation of GnRHR function.18 Males
with these mutations display signs of hypogonadism and small testes. Females typically
present with primary amenorrhea.19 Another important cause of IHH has been traced to
mutations in GPR54, which has a critical role in hypothalamic GnRH signaling and
release.20 Of note, both KS and IHH may be found in the same kindred. IHH has also been
noted to be reversible in some patients.21
Transcription factor mutations: Even with intact GnRH production and signal
transduction, pituitary gonadotropin synthesis may still be deficient due to mutations in a
variety of transcription factors. An important transcription factor involved in the
developmental cascade of pituitary gonadotrope cells is Prop-1. Prop-1 is the prophet of the
pituitary transcription factor Pit 1, a paired-like homeodomain transcription factor that is
responsible for early embryonic pituitary development. Prop-1 gene mutations can result in
familial combined pituitary hormone deficiency including growth hormone deficiency,
central hypothyroidism, and hypogonadotropic hypogonadism.22 In one analysis of 8
members of a consanguineous family with Prop-1 gene mutations, all 8 family members had
gonadotropin deficiency and failure of spontaneous sexual maturation.23 There is also a
variable pattern of phenotypic expressivity associated with Prop-1 mutations, with different
deficiencies appearing at different time periods within the same family.
Like Prop-1, the transcription factor HESX1 is needed for normal pituitary development.24
Deficiencies in HESX1, initially identified in 1998, are a rare cause of septo-optic
dysplasia25 which may be associated with hypogonadotropic hypogonadism.26 Other
transcription factors implicated in rare cases of hypogonadotropic hypogonadism include
LHX427 and SOX 2.28 All patients with hypopituitarism, including idiopathic forms, are at
risk for hypogonadotropic hypogonadism.
Leptin and leptin receptor defects: Congenital leptin deficiency results from loss of
function mutations of the LEP gene, which encodes for the leptin protein. Leptin interacts
with the leptin receptor, a member of the interleukin-6 family of receptors. This interaction
stimulates the Jak-Stat pathway and leads to activation of downstream target genes. Leptin
deficiency acts as a sign of nutritional deprivation and results in the suppression of the
reproductive axis. Classic findings in individuals with leptin deficiency include hyperphagia,
obesity, and hypogonadotropic hypogonadism. Administration of leptin seemingly rectifies
these abnormalities.29 Leptin receptor (LEPR) abnormalities have a similar phenotype to
congenital leptin deficiency. Females with this mutation have hypogonadotropic
hypogonadism. These girls present with delayed puberty, lack of a pubertal growth spurt,
and reduced expression of secondary sexual characteristics. Some may have irregular
menses due to aromatization of subcutaneous fat to estrogen, which then stimulates uterine
hyperplasia. Males with leptin receptor mutations have hypogonadotropic hypogonadism
and diminished testosterone production.30
Syndromes—Numerous syndromes include neuroendocrine dysfunction as a potential

feature. Perhaps the best known is Prader-Willi syndrome (PWS), which is caused by a
genetic defect involving paternal chromosome 15, usually in the form of a microdeletion
within the long arm or maternal unipaternal disomy.31 Hypothalamic dysfunction is marked
in these patients as evidenced by their hypotonia, hyperphagia, and intermittent temperature
instability. The hypothalamic dysfunction also leads to hypogonadism and may be attributed
to an absence of or abnormal location of GnRH neurons. Early studies in individuals with
PWS revealed low circulating serum gonadotropins and in males, attenuated testosterone
response to human chorionic gonadotropin.32 Physical findings in boys include micropenis,
scrotal hypoplasia, cryptorchidism, and small testes. Either absent or delayed puberty may
ensue. In girls, findings may be less remarkable and include hypoplasia of the clitoris or
labia minora, primary amenorrhea, and delayed puberty.33 However, a wide spectrum of
hypogonadism exists in PWS, with some women achieving fertility without hormone
replacement therapy.34,35
Acquired Origins
Any significant CNS insult can result in acquired hypogonadotropic hypogonadism. Two of
the most common causes in children are traumatic brain injury and CNS tumors.
Traumatic brain injury—Traumatic brain injury (TBI) is an insult to the brain that results
in neurologic dysfunction. TBI can have significant neurocognitive, neuropsychological, and

neuroendocrine sequelae.36,37 Anterior pituitary insufficiency resulting from TBI has been
noted in the past, but is garnering more attention as a high prevalence of pituitary hormone
insufficiency has been demonstrated.38 Some retrospective studies indicate that
gonadotropin deficiency may be found in 90% to 95% of those with history of TBI,39
although prospective studies in adults have noted the prevalence to be far less. In one study,
hormonal evaluation was conducted on TBI patients at baseline (acute phase) and at 12
months. In the acute phase, approximately 42% of those evaluated had gonadotropin
deficiency. At the 12-month follow-up, many of these patients spontaneously recovered
reproductive function. The final prevalence of hypogonadism was 7.7%.40 It is clear that all
patients with a history of TBI require ongoing surveillance for pituitary problems, including
hypogonadotropic hypogonadism.
Central nervous system tumors—Intracranial injury can also occur as a result of CNS
tumors. In children, resultant hypogonadotropic hypogonadism can exist as a result of the
primary tumor or due to the therapeutic regimen needed to treat the lesion. In a prospective
study of 75 children with various CNS tumors, 13% had an abnormality in gonadotropin
secretion before initiation of therapy.41 In a retrospective study focusing on
craniopharyngioma, only 1 out of 64 patients had evidence of hypogonadism before
treatment. However, after surgical resection and adjuvant radiotherapy, 80% of those
evaluated at a pubertal age had evidence of hypogonadism.42 Gonadotropin deficiency and
delayed puberty are most likely in those who receive 40 Gy or more of radiation.43
Gonadotropin deficiency may continue to evolve for many years after irradiation, with rates
of total incidence ranging from 20% to 50%.44,45 Therefore, all children who have CNS
lesions should be monitored for gonadotropin deficiency and signs of pubertal delay.46
Hypothalamic amenorrhea—Hypothalamic amenorrhea is commonly associated with

eating disorders such as anorexia nervosa, and also occurs in elite female athletes. Clinical
manifestations include absence of menstrual cycles, increased exercise, and weight loss. In
these girls, suppression of GnRH secretion results in attenuation of LH and FSH release, and
decreased estrogen production.47 Several theories have been postulated for this
hypothalamic dysfunction, including low circulating energy levels due to high energy
expenditure and relative deficiency of nutritional intake.47 Girls with hypothalamic
amenorrhea also have low circulating leptin levels. Administration of recombinant leptin to
some women with hypothalamic amenorrhea leads to elevated LH and estradiol, resulting in
follicular growth and ovulation.48
HYPERGONADOTROPIC HYPOGONADISM
Primary hypogonadism can be due to congenital origins such as chromosomal abnormalities,
syndromes, or genetic mutations. Primary hypogonadism can also be acquired later in
childhood or adolescence due to autoimmunity or exposure to chemotherapy or radiation.
Alterations in gonadotropins, the gonadotropin receptors, or within the gonads themselves
can lead to hypogonadism with decreased testosterone and estradiol secretion. The
decreased sex steroid secretion causes increased production of gonadotropins manifesting as
hypergonadotropic hypogonadism. Congenital causes of primary hypogonadism are outlined
in Table 2.
Congenital Origins
The most common cause of congenital primary hypogonadism is sex chromosome
aneuploidy as is present in Turner syndrome and Klinefelter syndrome. Isolated
abnormalities of the X chromosome are also associated with primary ovarian failure.
Turner syndrome—Turner syndrome (TS) occurs in 1 in 2500 live born females.49

Diagnosis of the syndrome requires the combination of characteristic physical features,
including short stature as well as partial or complete absence of an X chromosome.50 More
than half of girls with TS have chromosomal mosaicism. Approximately 30% will begin
puberty spontaneously, but only a small minority will progress to menarche.51 Spontaneous
pregnancy has been reported but is extremely rare in this population.52 Although initially
intrinsically normal, the ovaries in girls with TS undergo accelerated atresia such that
ovarian failure is often already present and may be detected at birth. Precisely which genes
on the X chromosome are necessary for ovarian maintenance is unknown. FSH levels during
early life have been found to be significantly lower in girls with mosaic TS as compared
with those who are monosomic.53
Klinefelter syndrome—Klinefelter syndrome is the most common congenital cause of

primary hypogonadism and occurs in 1 in 1000 live male births.54 The most common
genotype is XXY, although variants exist with different numbers of X chromosomes. Tall
stature, a eunuchoid body habitus, gynecomastia, and small, firm testes are cardinal features.
Seminiferous tubule dysgenesis is a classic histologic feature of the testes. Individuals with
Klinefelter syndrome exhibit a spectrum of gonadal failure, with many men going
undiagnosed until they present with infertility in adulthood. However, a significant number
come to attention during adolescence due to delayed puberty or lack of appropriate pubertal
progression.
X chromosome abnormalities—Other X chromosome abnormalities, including Xq

deletion and Triple X, can cause varying degrees of hypogonadism. Xq deletion can cause a
phenotype similar to TS as well as isolated premature ovarian failure.55 Deletions in the

critical region, Xq13-q26, can also lead to premature ovarian failure.56 Triple X, 47 XXX, is
estimated to exist in 1 in 1000 girls and is marked by significant phenotypic variability.57
Women with this condition can be tall and have normal external genitalia, with preservation
of ovarian function.57 These women can also have ovarian failure as well as significant
genitourinary tract anomalies, including cloacal exstrophy and mullerian abnormalities.58,59
Abnormalities in gonadotropin production or action—Mutations within the β

subunit of the gonadotropins, the gonadotropin receptors, or forms of resistance to
gonadotropins can all result in hypergonadotropic hypogonadism. Females with mutations in
the β subunit of FSH present with primary amenorrhea, delayed puberty, and poorly
developed secondary sexual characteristics; they have low FSH levels, low estradiol levels,
and high LH levels due to lack of feedback inhibition by estradiol.60,61 Males with the same
mutation have normal to delayed puberty and azospermia.62
A homozygous mutation within the LH β subunit has resulted in total functional loss in one
male.63 The individual in this case presented with delayed puberty, low serum testosterone,
and high LH levels. It was discovered later that several male members in his family were
infertile. In further studies, it was noted that females with this defect present with ovarian
dysfunction, infertility, menstrual irregularity, or polycystic ovary syndrome.64
Inactivating mutations of the G-protein coupled FSH and LH receptors result in a phenotype
similar to those with abnormalities in the LH and FSH β subunits. Complete LH resistance
results from a loss of function mutation in the LH receptor gene. In males, this causes a
phenotype that ranges from micropenis, to ambiguous genitalia, to completely female
external genitalia.65,66 In females, LH resistance results in normal puberty but subsequent
amenorrhea, infertility, and elevated LH levels, demonstrating that ovulation requires LH as
well as FSH.67 FSH resistance due to FSH receptor mutations has also been reported,
particularly in the Finnish population. Women who are homozygous for this defect have
gonadal dysgenesis and primary amenorrhea.68 In contrast, men from the same kindreds
have variable degrees of infertility.
A rare congenital condition associated with gonadotropin resistance is carbohydrate-

deficient glycoprotein syndrome, which causes defects in gonadotropin glycosylation. In
females with this defect, FSH seems to have less bioactivity and leads to decreased serum
estradiol levels. However, exogenous FSH results in an increase in estradiol. Males with this
disease advance through puberty but have decreased testicular volume.69
Resistance syndromes can also be due to variations in the signal transduction pathway after
gonadotropin binding. Pseudohypoparathyroidism is a disease in which the signal
transduction pathway of many hormones is altered due to inactivating mutations of the Gs α
subunit. The mutation leads to multiple hormone resistance. In a study of 12 patients with
pseudohypoparathyroidism, 25% of the pubertal patients had evidence of gonadotropin
resistance.70
Disorders of sex development—Disorders of sex development (DSDs) are congenital

conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.71
This broad category includes common entities such as TS and Klinefelter Syndrome, as well
as rare disorders such as cloacal exstrophy, mixed gonadal dysgenesis, and congenital
aphallia. Many DSDs are associated with ambiguous genitalia, which is beyond the scope of
this review. However, a few may present with delayed puberty or primary amenorrhea, and
are important to consider in the differential diagnosis of an adolescent with apparent
hypogonadism. These DSDs include Swyer syndrome, complete androgen insensitivity
syndrome (CAIS), and rare forms of congenital adrenal hyperplasia (CAH), all of which
result in female external genitalia.
Swyer syndrome: Swyer syndrome, also known as XY pure gonadal dysgenesis, is

characterized by tall stature, primary amenorrhea, and delayed puberty in a phenotypic
female. Laboratory studies reveal elevated gonadotropins, and ultrasonographic examination
reveals bilateral streak gonads and a hypoplastic uterus.72 Fifteen to thirty percent of these
individuals have mutations in SRY (sex-determining region of the Y chromosome) or
alterations in the Y chromosome.73 There is also a high risk of gonadal tumors such as
dysgerminoma or gonadoblastoma.73 Therefore, gonadectomy is routinely recommended

when this diagnosis is made.
Complete androgen insensitivity syndrome: CAIS is caused by mutations of the androgen

receptor that result in loss of testosterone and dihydrotestosterone mediated action.
Androgen receptor mutations are X-linked recessive in 70% of cases, and are found in 1 in
20,000 to 1 in 90,000 genetic males.74 The most common phenotype is that of an adolescent
girl who has normal breast development, but absent or scant body hair and primary
amenorrhea. Examination of the external genitalia reveals a normal female phenotype with a
blind ending vagina. Eighty percent to 90% of girls with CAIS will also eventually develop
inguinal hernias,75 with some presenting in infancy with this diagnosis.
Congenital adrenal hyperplasia: Rare forms of CAH can present with hypogonadism due
to lack of production of testosterone and estrogen. These conditions include deficiencies of
17α-hydroxylase, side chain cleavage enzyme (SCC), and steroid acute regulatory protein
(StAR). Girls with 17α-hydroxylase deficiency can present with primary amenorrhea and
absent secondary sexual characteristics. Boys have female external genitalia, a blind vagina,
and intra-abdominal testes.76 Hypertension and hypokalemia may also be present.77 SCC is
the first step in the steroidogenic pathway and converts cholesterol to pregnenolone. SCC
deficiency leads to deficiencies in all steroid hormones. SCC deficiency in genetic males
leads to XY sex reversal and adrenal insufficiency.78 StAR, a protein expressed in the
adrenal cortex and gonads, increases cholesterol transport in response to steroidogenic
stimuli. Affected genetic males present in early infancy with adrenal crisis, and appear
phenotypically female.79 Affected genetic females are normally developed at birth and may
have intact ovarian function.80
Galactosemia: Another congenital cause of primary hypogonadism is galactosemia.

Galactosemia results from a deficiency in galactose-1-phosphate uridyltransferase (GALT)
and presents with clinical manifestations of cataracts, Escherichia coli sepsis, poor growth,
and feeding dysfunction if undiagnosed in the newborn. In an initial study conducted in
1981, gonadal function was evaluated in 12 women and 8 men with galactosemia. Although
gonadal function was normal in men with the disease, the women in this study had evidence
of hypergonadotropic hypogonadism, with varying degrees of primary and secondary
amenorrhea and oligomenorrhea.81 Ultrasound studies of the ovaries in those affected
demonstrated streak gonads in several women.81 The cause of the hypogonadism is most
likely premature ovarian failure, although the exact pathophysiology is not well understood.
Numerous theories exist, including the hypothesis that galactose-1-phosphate is toxic and
perhaps competitively inhibits UDP-Galactose transferase and alters FSH and FSH
receptors, with subsequent failure of ovarian follicles to develop.82 This process manifests
as an elevated FSH in 85% of girls younger than 10 years who have galactosemia and
premature ovarian failure.82
Testicular regression sequence: Testicular regression sequence (TRS), or vanishing testis

syndrome, occurs when an initially normal testicle that existed in fetal life subsequently
atrophies. Most individuals with TRS have normal male external genitalia, reflecting that
normal testicular function existed during prenatal life. The most likely cause of this
syndrome is fetal or antenatal testicular torsion, or trauma to scrotal contents in utero.83 This
view is supported by the finding of hemosiderin laden macrophages and dystrophic
calcifications under histopatholgic examination.84 There has also been an association noted
between testicular regression and persistence of mullerian duct structures.85 Thus far, a
search for a molecular genetic cause of TRS has been negative.86
Acquired Origins
The acquired forms of primary hypogonadism are as varied as the congenital forms.
Important acquired origins include treatment for pediatric cancer (radiation and
chemotherapy) and autoimmune conditions.
Chemotherapy and radiation—Both chemotherapy and radiation have been noted to

cause primary hypogonadism. In girls, the dose of intra-abdominal radiation needed to
destroy more than 50% of developing oocytes is less than 2 Gy.87 In the 70% of patients
who survive pediatric cancer, 1 in 6 female survivors develops primary ovarian failure.
Those who do undergo spontaneous menarche have decreased ovarian reserve.88 In boys,
depressed spermatogenesis can be seen after a testicular radiation dose as low as 0.15 Gy,
with temporary azoospermia occurring after doses of 0.3 Gy.89 The effect of radiation on
testicular function is age dependent, with prepubertal radiation exposure causing
significantly more damage to Leydig cells than postpubertal radiation.90 Cumulative doses
of alkylating agents are also correlated with altered function.89
A high prevalence of hypogonadism was noted in young adult survivors of childhood cancer
who participated in a study comparing 3 treatment arms for non-Hodgkin lymphoma (NHL)
and acute lymphoblastic leukemia (ALL). The study compared treatment with chemotherapy
alone (vincristine, prednisolone, l-asparaginase, methotrexate, 6-mercaptopurine), combined
chemotherapy and prophylactic cranial radiation, and chemotherapy with total body
radiation and bone marrow transplant. All women in the third category had premature
ovarian failure. Women in the other 2 categories, however, had intact ovarian function.
Among men in the third category, 83% had primary hypogonadism, with a low serum
testosterone and elevated FSH and LH. Forty percent of men in all 3 treatment arms had
alterations in spermatogenesis, with the greatest dysfunction appearing in those who had
received total body radiation.91
Despite these findings, there have been reports of spontaneous recovery of testicular or
ovarian function in childhood cancer survivors. Although more common in older children
and adults, recovery of ovarian function has occurred as long as 12 years post exposure to
radiation and alkylating chemotherapy in a young girl.92 Due to the increased risk of
gonadal dysfunction in pediatric cancer patients and also due to the chance of spontaneous
recovery, recommendations for surveillance include yearly monitoring of pubertal status
with Tanner staging and assessment of growth velocity. Laboratory measurements of FSH
and LH as well as estradiol or testosterone are recommended for those with signs of pubertal
delay.93
Autoimmune gonadal failure—Autoimmunity can lead to both testicular and ovarian

failure, specifically in those who have other types of autoimmune endocrinopathies. Several
autoimmune polyglandular syndromes (APS) have been identified. Of these, APS I and APS
II have been associated with premature ovarian failure at prevalence rates of 30% to 50%.94
APS I consists of a triad of hypoparathyroidism, mucocutaneous candidiasis, and adrenal
insufficiency. The mutation is within the AIRE gene, the autoimmune regulator. In a Finnish
cohort, approximately 50% of the females identified with APS I had premature ovarian
failure. Two-thirds of these individuals had autoantibodies to side-chain cleavage enzyme
(anti-SCC),95 one of the enzymes identified in steroid production that is specific to the ovary
and is noted in autoimmune ovarian failure. In those who have been diagnosed with APS I
and who initially have signs of ovarian failure, the presence of steroid cell antibodies may
signal progression of the disease process.96 APS II consists of autoimmune adrenocortical
failure along with thyroid disease or diabetes. Positive antibodies to the P450 enzymes,
specifically ovary-specific antibodies, in the steroid production pathway are thought to

mediate autoimmune ovarian failure in this syndrome as well.97 Autoimmunity can also
cause isolated premature ovarian failure,98 and has also been reported in conditions such as
systemic lupus erythematous and myasthenia gravis.
Testicular failure occurs at a lower rate than ovarian failure in APS.99 Autoimmunity to the
Leydig cells in APS may be mediated by P450 autoantibodies that are testis specific.100
Antisperm antibodies have also been noted in prepubertal boys treated with chemotherapy
and in those with urogenital tract abnormalities such as cryptorchidism, testicular torsion, or
hypospadias.101
EVALUATION
Evaluation of a child with delayed puberty begins with a careful history and physical
examination. Important elements on history include the parents’ pubertal timing, because
late menarche in the mother or delayed completion of adult height in the father is strongly
suggestive of CDGP. Eliciting a family history of hypogonadism, autoimmune syndromes,
DSDs, or consanguinity is also essential. History in the child should include attention to any
CNS insult or symptoms of chronic disease. In the review of systems, lack of sense of smell
can be an important clue to the presence of KS.
Physical examination should include height and weight measurements. Neurologic

assessment should include evaluation of visual fields. Assessment of secondary sexual
characteristics includes Tanner staging and recognition of evidence of androgen exposure.
Testicular enlargement, which can sometimes go unnoticed by boys, indicates the onset of
central puberty. Stigmata of TS or Klinefelter Syndrome should be noted. The external
genitalia should be visually inspected for any signs of anatomic abnormality.
Laboratory evaluation including plasma gonadotropin levels, estradiol, or testosterone may

be helpful. Low gonadotropin levels suggest CDGP or pathologic hypogonadotropic
hypogonadism, and can be further evaluated with a GnRH stimulation test.102 In contrast,
elevated gonadotropins indicate primary gonadal failure. A bone age radiograph is an
essential component of the evaluation. Other tests that may be indicated, depending on the
individual situation, include a head MRI, karyotype, auto-immune panel, or molecular
genetic analysis. In patients with suspected CDGP, a “wait and see” approach is typically
employed to determine whether spontaneous puberty will ensue.
TREATMENT
Although there are many causes of hypogonadism in children, the treatment is primarily
focused on hormone replacement with sex steroids. The overarching goal is to simulate a
normal progression of pubertal development that also allows for the attainment of genetic
potential for height.
Estrogen Replacement
Estrogen therapy is initially started for pubertal induction and breast development in girls
with hypogonadism. Studies regarding estrogen therapy in children have focused primarily
on girls with TS. Recommended starting doses of estrogen therapy in this population are
one-eighth to one-tenth the doses used for adult replacement, and vary depending on the
formulation used. Very low doses have been reported to have a salutary effect on linear
growth in TS.103 Multiple different formulations of estrogen are available, and include oral
estradiol, oral conjugated estrogen, trans-dermal estrogen patches, and estrogen gel. The age
at which estrogen therapy is initiated is individualized and incorporates factors such as
chronologic age, bone age, absolute height, and psychosocial issues. The starting dose is low
and is gradually increased over several years. Equivalent adult doses of oral therapy are
micronized estradiol, 2 mg, esterified estrogen, 1.25 mg, ethinyl estradiol, 8 to 10 μg, and
conjugated estrogens, 1.25 mg.104 Addition of progesterone 1 week per month, usually in
the form of medroxyprogesterone, after 1 to 2 years of estrogen therapy or post
breakthrough bleeding, allows for adequate breast and uterine development. Formulations
and available does of estrogen preparations are shown in Table 3.
Limitations of oral estrogen therapy include variable bioavailability due to first-pass

metabolism within the liver, which subsequently affects liver function and clotting
factors.105,106 As a result, transdermal estrogen formulations are gaining in popularity.
Estrogen patches are widely used in adult women, and doses of 0.625 and 1.25 mg of oral
conjugated estrogens have been reported to be similar those of 50 and 100 μg of transdermal
estradiol per 24 hours.107 Pubertal induction can be accomplished with transdermal estradiol
at a dose as low as 3.1 to 6.2 μg/24 hours.106 Puberty can then be mimicked with subsequent
doubling of the dose after a median duration of 8 months and addition of progesterone 2
years after estrogen initiation. A transdermal estrogen dose of 0.1 mg/d is equivalent to an
adult regimen. When comparing transdermal estrogen to oral estrogen, significantly higher
levels of 17β-estradiol were noted with oral estrogen. However, no differences in metabolic
effects including lipolysis, lipid, and carbohydrate oxidation, and resting energy expenditure
from short-term transdermal versus oral estrogen therapy have been noted.105 In contrast, a
pilot study of transdermal versus oral conjugated estrogen in girls with TS found better bone
mineral accrual and uterine development in the transdermal group.108 Percutaneous estradiol
gel has also been investigated for pubertal induction in girls with TS at a starting dose of 0.1
mg nightly with increases of 0.1 mg for each additional year up to 5 years. Side effects of
percutaneous gel therapy include local skin irritation, and this modality is not currently in
use in the clinical setting.109 For hypogonadal women, estrogen replacement is needed
throughout reproductive life.
Testosterone Replacement
In boys, studies involving testosterone for pubertal induction have primarily focused on
CDGP and KS. Testosterone therapy is usually initiated at 15% to 25% of adult doses.
Approximately 50 to 100 mg of a testosterone ester formulation is given intra-muscularly
every 2 to 4 weeks for 4 to 6 months with gradual increases to adult doses.110,111 In boys
with CDGP, a 4- to 6-month course of 50 to 100 mg testosterone per month may be offered
to bring about initial secondary sexual characteristics and boost linear growth.110 In boys
who have permanent hypogonadism, the need for therapy is lifelong. Even at the initial
doses used for pubertal induction, there is a decrease in total fat mass, percent body fat, and
whole body proteolysis once testosterone is initiated.112
Intramuscular, transdermal, and oral formulations of testosterone exist. The preparations

testosterone enanthate and testosterone cypionate are the most often used formulations in
children, due to the difficulty in delivering the small doses needed initially for pubertal
induction with alternate forms.113 Intramuscular injections of testosterone, however, can be

painful for the adolescent patient population, and studies investigating other formulations
are ongoing.
Formal guidelines regarding the use of oral preparations have yet to be delineated, and
experience with this form of testosterone is far less than with the intramuscular form.
Transdermal testosterone, in the form of testosterone gel, at doses of 50 mg/m2/d has been
used in children short-term to treat poor growth secondary to renal failure.114 In a study of
transdermal testosterone delivered via a 5-mg patch, overnight use in boys with delayed
puberty resulted in pubertal testosterone concentrations as well short-term growth.115 Side
effects of transdermal testosterone include local skin irritation. As in oral testosterone
therapy, there are limited studies regarding the use of transdermal preparations of
testosterone, and intramuscular testosterone therapy remains the mainstay of therapy for
pediatric patients. Testosterone preparations and adult doses are shown in Table 4.
Adjunctive treatment in the form of human chorionic gonadotropin has been suggested in
boys with PWS in whom beneficial effects on body composition and endogenous
testosterone secretion have been observed.116
SUMMARY
In conclusion, causes of hypogonadism are heterogeneous and may involve any level of the
reproductive system. Whereas some conditions are clearly delineated, the exact etiology and
underlying pathogenesis of many disorders is unknown. Regardless of the form of
hypogonadism, the crux of therapy in children revolves around sex steroid replacement.
Continued molecular genetic investigation and prospective clinical trials will enhance
knowledge and improve management of hypogonadism in pediatric patients.
References
1. Boyar R, Finkelstein J, Roffwarg H, et al. Synchronization of augmented luteinizing hormone
secretion with sleep during puberty. N Engl J Med. 1972; 287(12):582–6. [PubMed: 4341276]
2. Apter D, Butzow TL, Laughlin GA, et al. Gonadotropin-releasing hormone pulse generator activity
during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins. J Clin
Endocrinol Metab. 1993; 76(4):940–9. [PubMed: 8473410]
3. Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic
center. J Clin Endocrinol Metab. 2002; 87(4):1613–20. [PubMed: 11932291]
4. von Kalckreuth G, Haverkamp F, Kessler M, et al. Constitutional delay of growth and puberty: do
they really reach their target height? Horm Res. 1991; 35(6):222–5. [PubMed: 1819545]
5. Bergada I, Bergada C. Long term treatment with low dose testosterone in constitutional delay of
growth and puberty: effect on bone age maturation and pubertal progression. J Pediatr Endocrinol
Metab. 1995; 8(2):117–22. [PubMed: 7584705]
6. Achermann JC, Weiss J, Lee EJ, et al. Inherited disorders of the gonadotropin hormones. Mol Cell
Endocrinol. 2001; 179(1–2):89–96. [PubMed: 11420133]
7. Kohler B, Lin L, Ferraz-de-Souza B, et al. Five novel mutations in steroidogenic factor 1 (SF1,
NR5A1) in 46, XY patients with severe underandrogenization but without adrenal insufficiency.
Hum Mutat. 2008; 29(1):59–64. [PubMed: 17694559]
8. Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with
transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency.
Am J Hum Genet. 2000; 67(6):1563–8. [PubMed: 11038323]
9. Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX-1 gene give rise to both X-linked
adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994; 372(6507):672–
6. [PubMed: 7990958]
10. Yang F, Hanaki K, Kinoshita T, et al. Late-onset adrenal hypoplasia congenita caused by a novel
mutation of the DAX-1 gene. Eur J Pediatr. 2009; 168:329–31. [PubMed: 18607630]
11. Habiby RL, Boepple P, Nachtigall L, et al. Adrenal hypoplasia congenita with hypogonadotropic
hypogonadism: evidence that DAX-1 mutations lead to combined hypothalamic and pituitary
defects in gonadotropin production. J Clin Invest. 1996; 98(4):1055–62. [PubMed: 8770879]
12. Mantovani G, De Menis E, Borretta G, et al. DAX1 and X-linked adrenal hypoplasia congenita:
clinical and molecular analysis in five patients. Eur J Endocrinol. 2006; 154(5):685–9. [PubMed:
16645015]
13. Franco B, Guioli S, Pragliola A, et al. A gene deleted in Kallmann’s syndrome shares homology
with neural cell adhesion and axonal path-finding molecules. Nature. 1991; 353(6344):529–36.
[PubMed: 1922361]
14. Vogl TJ, Stemmler J, Heye B, et al. Kallman syndrome versus idiopathic hypogonadotropic
hypogonadism at MR imaging. Radiology. 1994; 191(1):53–7. [PubMed: 8134597]

15. Oliveira LM, Seminara SB, Beranova M, et al. The importance of autosomal genes in Kallmann
syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol
Metab. 2001; 86(4):1532–8. [PubMed: 11297579]
16. Sato N, Katsumata N, Kagami M, et al. Clinical assessment and mutation analysis of Kallmann
syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families
and 18 sporadic patients. J Clin Endocrinol Metab. 2004; 89(3):1079–88. [PubMed: 15001591]
17. Pitteloud N, Zhang C, Pignatelli D, et al. Loss-of-function mutation in the prokineticin 2 gene
causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl
Acad Sci U S A. 2007; 104(44):17447–52. [PubMed: 17959774]
18. de Roux N, Young J, Misrahi M, et al. A family with hypogonadotropic hypogonadism and
mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997; 337(22):1597–
602. [PubMed: 9371856]
19. de Roux N, Milgrom E. Inherited disorders of GnRH and gonadotropin receptors. Mol Cell
Endocrinol. 2001; 179(1–2):83–7. [PubMed: 11420132]
20. de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of
the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003; 100(19):10972–6.
[PubMed: 12944565]
21. Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N
Engl J Med. 2007; 357(9):863–73. [PubMed: 17761590]

22. Pfaffle RW, Blankenstein O, Wuller S, et al. Combined pituitary hormone deficiency: role of Pit-1
and Prop-1. Acta Paediatr Suppl. 1999; 88(433):33–41. [PubMed: 10626543]
23. Lazar L, Gat-Yablonski G, Kornreich L, et al. PROP-1 gene mutation (R120C) causing combined
pituitary hormone deficiencies with variable clinical course in eight siblings of one Jewish
Moroccan family. Horm Res. 2003; 60(5):227–31. [PubMed: 14614227]
24. Dasen JS, Barbera JP, Herman TS, et al. Temporal regulation of a paired-like homeodomain
repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis.
Genes Dev. 2001; 15(23):3193–207. [PubMed: 11731482]
25. Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESX1/
Hesx1 associated with septooptic dysplasia in human and mouse. Nat Genet. 1998; 19(2):125–33.
[PubMed: 9620767]
26. Haddad NG, Eugster EA. Hypopituitarism and neurodevelopmental abnormalities in relation to
central nervous system structural defects in children with optic nerve hypoplasia. J Pediatr
27. Pfaeffle RW, Hunter CS, Savage JJ, et al. Three novel missense mutations within the LHX4 gene
are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab. 2008; 93(3):
1062–71. [PubMed: 18073311]
28. Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with
abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest. 2006;
116(9):2442–55. [PubMed: 16932809]
29. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity, Tcell
hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin
deficiency. J Clin Invest. 2002; 110(8):1093–103. [PubMed: 12393845]
30. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital
deficiency of the leptin receptor. N Engl J Med. 2007; 356(3):237–47. [PubMed: 17229951]
31. Wharton RH, Loechner KJ. Genetic and clinical advances in Prader-Willi syndrome. Curr Opin
Pediatr. 1996; 8(6):618–24. [PubMed: 9018447]
32. Jeffcoate WJ, Laurance BM, Edwards CR, et al. Endocrine function in the Prader-Willi syndrome.
Clin Endocrinol (Oxf). 1980; 12(1):81–9. [PubMed: 6769611]
33. Crino A, Schiaffini R, Ciampalini P, et al. Hypogonadism and pubertal development in Prader-
Willi syndrome. Eur J Pediatr. 2003; 162(5):327–33. [PubMed: 12692714]
34. Schulze A, Mogensen H, Hamborg-Petersen B, et al. Fertility in Prader-Willi syndrome: a case
report with Angelman syndrome in the offspring. Acta Paediatr. 2001; 90(4):455–9. [PubMed:
11332942]
35. Akefeldt A, Tornhage CJ, Gillberg C. A woman with Prader-Willi syndrome gives birth to a
healthy baby girl. Dev Med Child Neurol. 1999; 41(11):789–90. [PubMed: 10576646]
36. Morton MV, Wehman P. Psychosocial and emotional sequelae of individuals with traumatic brain
injury: a literature review and recommendations. Brain Inj. 1995; 9(1):81–92. [PubMed: 7874099]
37. Kelly DF, Gonzalo IT, Cohan P, et al. Hypopituitarism following traumatic brain injury and
aneurysmal subarachnoid hemorrhage: a preliminary report. J Neurosurg. 2000; 93(5):743–52.
[PubMed: 11059653]
38. Lieberman SA, Oberoi AL, Gilkison CR, et al. Prevalence of neuroendocrine dysfunction in
patients recovering from traumatic brain injury. J Clin Endocrinol Metab. 2001; 86(6):2752–6.
[PubMed: 11397882]
39. Benvenga S, Campenni A, Ruggeri RM, et al. Clinical review 113: hypopituitarism secondary to
head trauma. J Clin Endocrinol Metab. 2000; 85(4):1353–61. [PubMed: 10770165]
40. Tanriverdi F, Senyurek H, Unluhizarci K, et al. High risk of hypopituitarism after traumatic brain
injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months
after trauma. J Clin Endocrinol Metab. 2006; 91(6):2105–11. [PubMed: 16522687]
41. Merchant TE, Williams T, Smith JM, et al. Preirradiation endocrinopathies in pediatric brain tumor
patients determined by dynamic tests of endocrine function. Int J Radiat Oncol Biol Phys. 2002;
54(1):45–50. [PubMed: 12182973]
42. Gonc EN, Yordam N, Ozon A, et al. Endocrinological outcome of different treatment options in
children with craniopharyngioma: a retrospective analysis of 66 cases. Pediatr Neurosurg. 2004;
40(3):112–9. [PubMed: 15367800]
43. Mills JL, Fears TR, Robison LL, et al. Menarche in a cohort of 188 long-term survivors of acute
lymphoblastic leukemia. J Pediatr. 1997; 131(4):598–602. [PubMed: 9386666]
44. Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain
tumors. N Engl J Med. 1993; 328(2):87–94. [PubMed: 8416438]
45. Rappaport R, Brauner R, Czernichow P, et al. Effect of hypothalamic and pituitary irradiation on
pubertal development in children with cranial tumors. J Clin Endocrinol Metab. 1982; 54(6):1164–
8. [PubMed: 6804477]
46. Nandagopal R, Laverdiere C, Mulrooney D, et al. Endocrine late effects of childhood cancer
therapy: a report from the Children’s Oncology Group. Horm Res. 2008; 69(2):65–74. [PubMed:
18059086]
47. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and
clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. 2005;
366(9479):74–85. [PubMed: 15993236]
48. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic
amenorrhea. N Engl J Med. 2004; 351(10):987–97. [PubMed: 15342807]
49. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results
from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991; 87(1):81–3. [PubMed:
2037286]
50. Bondy CA. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome
Study Group. J Clin Endocrinol Metab. 2007; 92(1):10–25. [PubMed: 17047017]
51. Pasquino AM, Passeri F, Pucarelli I, et al. Italian Study Group for Turner’s Syndrome.
Spontaneous pubertal development in Turner’s syndrome. J Clin Endocrinol Metab. 1997; 82(6):
1810–3. [PubMed: 9177387]
52. Hovatta O. Pregnancies in women with Turner’s syndrome. Ann Med. 1999; 31(2):106–10.
[PubMed: 10344582]
53. Fechner PY, Davenport ML, Qualy RL, et al. Differences in follicle-stimulating hormone secretion
between 45, X monosomy Turner syndrome and 45, X/46, XX mosaicism are evident at an early
age. J Clin Endocrinol Metab. 2006; 91(12):4896–902. [PubMed: 16968797]
54. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a
national registry study. J Clin Endocrinol Metab. 2003; 88(2):622–6. [PubMed: 12574191]
55. Abulhasan SJ, Tayel SM, al-Awadi SA. Mosaic Turner syndrome: cytogenetics versus FISH. Ann
Hum Genet. 1999; 63(Pt 3):199–206. [PubMed: 10738532]

56. Rizzolio F, Bione S, Sala C, et al. Chromosomal rearrangements in Xq and premature ovarian
failure: mapping of 25 new cases and review of the literature. Hum Reprod. 2006; 21(6):1477–83.
[PubMed: 16497693]
57. Linden MG, Bender BG, Harmon RJ, et al. 47, XXX: what is the prognosis? Pediatrics. 1988;
82(4):619–30. [PubMed: 2459656]
58. Lin HJ, Ndiforchu F, Patell S. Exstrophy of the cloaca in a 47, XXX child: review of genitourinary
malformations in triple-X patients. Am J Med Genet. 1993; 45(6):761–3. [PubMed: 8456857]
59. Holland CM. 47, XXX in an adolescent with premature ovarian failure and auto-immune disease. J
Pediatr Adolesc Gynecol. 2001; 14(2):77–80. [PubMed: 11479104]
60. Matthews CH, Borgato S, Beck-Peccoz P, et al. Primary amenorrhoea and infertility due to a
mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993; 5(1):83–6.
[PubMed: 8220432]
61. Layman LC, Lee EJ, Peak DB, et al. Delayed puberty and hypogonadism caused by mutations in
the follicle-stimulating hormone beta-subunit gene. N Engl J Med. 1997; 337(9):607–11.
[PubMed: 9271483]
62. Lindstedt G, Nystrom E, Matthews C, et al. Follitropin (FSH) deficiency in an infertile male due to
FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped
testicles with azoospermia, low FSH but high lutropin and normal serum testosterone
concentrations. Clin Chem Lab Med. 1998; 36(8):663–5. [PubMed: 9806482]
63. Weiss J, Axelrod L, Whitcomb RW, et al. Hypogonadism caused by a single amino acid
substitution in the beta subunit of luteinizing hormone. N Engl J Med. 1992; 326(3):179–83.
[PubMed: 1727547]
64. Furui K, Suganuma N, Tsukahara S, et al. Identification of two point mutations in the gene coding
luteinizing hormone (LH) beta-subunit, associated with immunologically anomalous LH variants.
J Clin Endocrinol Metab. 1994; 78(1):107–13. [PubMed: 7904610]
65. Kremer H, Kraaij R, Toledo SP, et al. Male pseudohermaphroditism due to a homozygous
missense mutation of the luteinizing hormone receptor gene. Nat Genet. 1995; 9(2):160–4.
[PubMed: 7719343]
66. Latronico AC, Anasti J, Arnhold IJ, et al. Brief report: testicular and ovarian resistance to
luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N
Engl J Med. 1996; 334(8):507–12. [PubMed: 8559204]
67. Arnhold IJ, Latronico AC, Batista MC, et al. Clinical features of women with resistance to
luteinizing hormone. Clin Endocrinol (Oxf). 1999; 51(6):701–7. [PubMed: 10619974]
68. Aittomaki K. The genetics of XX gonadal dysgenesis. Am J Hum Genet. 1994; 54(5):844–51.
[PubMed: 8178824]
69. de Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1
from birth through adolescence. Pediatr Res. 1995; 37(4 Pt 1):395–401. [PubMed: 7596677]
70. Gelfand IM, Eugster EA, DiMeglio LA. Presentation and clinical progression of
pseudohypoparathyroidism with multi-hormone resistance and Albright hereditary osteodystrophy:
a case series. J Pediatr. 2006; 149(6):877–80. [PubMed: 17137912]
71. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders.
International Consensus Conference on Intersex Pediatrics. 2006; 118(2):e488–500.
72. Michala L, Goswami D, Creighton SM, et al. Swyer syndrome: presentation and outcomes. BJOG.
May; 2008 115(6):737–41. [PubMed: 18410658]
73. Zielinska D, Zajaczek S, Rzepka-Gorska I. Tumors of dysgenetic gonads in Swyer syndrome. J
Pediatr Surg. 2007; 42(10):1721–4. [PubMed: 17923202]
74. Oakes MB, Eyvazzadeh AD, Quint E, et al. Complete androgen insensitivity syndrome—a review.
J Pediatr Adolesc Gynecol. 2008; 21(6):305–10. [PubMed: 19064222]
75. Sarpel U, Palmer SK, Dolgin SE. The incidence of complete androgen insensitivity in girls with
inguinal hernias and assessment of screening by vaginal length measurement. J Pediatr Surg. 2005;
40(1):133–6. discussion: 136–7. [PubMed: 15868573]
76. Costa-Santos M, Kater CE, Auchus RJ. Two prevalent CYP17 mutations and genotype-phenotype
correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab.

2004; 89(1):49–60. [PubMed: 14715827]
77. Yang J, Cui B, Sun S, et al. Phenotype-genotype correlation in eight Chinese 17alpha-hydroxylase/
17,20 lyase-deficiency patients with five novel mutations of CYP17A1 gene. J Clin Endocrinol
Metab. 2006; 91(9):3619–25. [PubMed: 16772352]
78. al Kandari H, Katsumata N, Alexander S, et al. Homozygous mutation of P450 side-chain cleavage
enzyme gene (CYP11A1) in 46, XY patient with adrenal insufficiency, complete sex reversal, and
agenesis of corpus callosum. J Clin Endocrinol Metab. 2006; 91(8):2821–6. [PubMed: 16705068]
79. Baker BY, Lin L, Kim CJ, et al. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder
of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia.
J Clin Endocrinol Metab. 2006; 91(12):4781–5. [PubMed: 16968793]
80. Fujieda K, Tajima T, Nakae J, et al. Spontaneous puberty in 46, XX subjects with congenital lipoid
adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating
mutations in the steroidogenic acute regulatory protein (StAR) gene. J Clin Invest. 1997; 99(6):
1265–71. [PubMed: 9077535]
81. Kaufman FR, Kogut MD, Donnell GN, et al. Hypergonadotropic hypogonadism in female patients
with galactosemia. N Engl J Med. 1981; 304(17):994–8. [PubMed: 6782485]
82. Prestoz LL, Couto AS, Shin YS, et al. Altered follicle stimulating hormone isoforms in female
galactosaemia patients. Eur J Pediatr. 1997; 156(2):116–20. [PubMed: 9039515]

83. Smith NM, Byard RW, Bourne AJ. Testicular regression syndrome—a pathological study of 77
cases. Histopathology. 1991; 19(3):269–72. [PubMed: 1916702]
84. Law H, Mushtaq I, Wingrove K, et al. Histopathological features of testicular regression
syndrome: relation to patient age and implications for management. Fetal Pediatr Pathol. 2006;
25(2):119–29. [PubMed: 16908461]
85. Imbeaud S, Rey R, Berta P, et al. Testicular degeneration in three patients with the persistent
mullerian duct syndrome. Eur J Pediatr. 1995; 154(3):187–90. [PubMed: 7758514]
86. Vinci G, Anjot MN, Trivin C, et al. An analysis of the genetic factors involved in testicular descent
in a cohort of 14 male patients with anorchia. J Clin Endocrinol Metab. 2004; 89(12):6282–5.
[PubMed: 15579790]
87. Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod.
2003; 18(1):117–21. [PubMed: 12525451]
88. Larsen EC, Muller J, Schmiegelow K, et al. Reduced ovarian function in long-term survivors of
radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab. 2003; 88(11):
5307–14. [PubMed: 14602766]
89. Lopez Andreu JA, Fernandez PJ, Ferris i Tortajada J, et al. Persistent altered spermatogenesis in
long-term childhood cancer survivors. Pediatr Hematol Oncol. 2000; 17(1):21–30. [PubMed:
10689712]
90. Shalet SM, Tsatsoulis A, Whitehead E, et al. Vulnerability of the human Leydig cell to radiation
damage is dependent upon age. J Endocrinol. 1989; 120(1):161–5. [PubMed: 2493061]
91. Steffens M, Beauloye V, Brichard B, et al. Endocrine and metabolic disorders in young adult
survivors of childhood acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL).
Clin Endocrinol (Oxf). 2008; 69(5):819–27. [PubMed: 18429947]
92. Rahhal SN, Eugster EA. Unexpected recovery of ovarian function many years after bone marrow
transplantation. J Pediatr. 2008; 152(2):289–90. [PubMed: 18206705]
93. Meacham LR, Ghim TT, Crocker IR, et al. Systematic approach for detection of endocrine
disorders in children treated for brain tumors. Med Pediatr Oncol. 1997; 29(2):86–91. [PubMed:
9180908]
94. Schatz DA, Winter WE. Autoimmune polyglandular syndrome. II: clinical syndrome and
treatment. Endocrinol Metab Clin North Am. 2002; 31(2):339–52. [PubMed: 12092454]
95. Wolff AS, Erichsen MM, Meager A, et al. Autoimmune polyendocrine syndrome type 1 in
Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator
gene. J Clin Endocrinol Metab. 2007; 92(2):595–603. [PubMed: 17118990]
96. Ahonen P, Miettinen A, Perheentupa J. Adrenal and steroidal cell antibodies in patients with
autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J Clin
97. Uibo R, Aavik E, Peterson P, et al. Autoantibodies to cytochrome P450 enzymes P450scc,
P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated
Addison’s disease. J Clin Endocrinol Metab. 1994; 78(2):323–8. [PubMed: 8106620]
98. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity.
Endocr Rev. 1997; 18(1):107–34. [PubMed: 9034788]
99. Buzi F, Badolato R, Mazza C, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome: time to review diagnostic criteria? J Clin Endocrinol Metab. 2003; 88(7):
3146–8. [PubMed: 12843157]
100. Perniola R, Falorni A, Clemente MG, et al. Organ-specific and non-organ-specific autoantibodies
in children and young adults with autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy (APECED). Eur J Endocrinol. 2000; 143(4):497–503. [PubMed: 11022196]
101. Sinisi AA, D’Apuzzo A, Pasquali D, et al. Antisperm antibodies in prepubertal boys treated with
chemotherapy for malignant or non-malignant diseases and in boys with genital tract
abnormalities. Int J Androl. 1997; 20(1):23–8. [PubMed: 9202987]
102. Goodpasture JC, Ghai K, Cara JF, et al. Potential of gonadotropin-releasing hormone agonists in
the diagnosis of pubertal disorders in girls. Clin Obstet Gynecol. 1993; 36(3):773–85. [PubMed:
8403624]
103. Rosenfield RL, Perovic N, Devine N, et al. Optimizing estrogen replacement treatment in Turner
syndrome. Pediatrics. 1998; 102(2 Pt 3):486–8. [PubMed: 9685449]
104. Donaldson MD, Gault EJ, Tan KW, et al. Optimising management in Turner syndrome: from
infancy to adult transfer. Arch Dis Child. 2006; 91(6):513–20. [PubMed: 16714725]
105. Mauras N, Shulman D, Hsiang HY, et al. Metabolic effects of oral versus trans-dermal estrogen
in growth hormone-treated girls with turner syndrome. J Clin Endocrinol Metab. 2007; 92(11):
4154–60. [PubMed: 17711924]
106. Ankarberg-Lindgren C, Elfving M, Wikland KA, et al. Nocturnal application of transdermal
estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous
puberty in girls. J Clin Endocrinol Metab. 2001; 86(7):3039–44. [PubMed: 11443165]
107. Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N
Engl J Med. 1986; 314(25):1615–20. [PubMed: 3012339]
108. Nabhan ZM, DiMeglio LA, Qi R, et al. Oral versus transdermal estrogen replacement in girls
with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab. 2009; 94(6):2009–
14. [PubMed: 19318455]
109. Piippo S, Lenko H, Kainulainen P, et al. Use of percutaneous estrogen gel for induction of
puberty in girls with Turner syndrome. J Clin Endocrinol Metab. 2004; 89(7):3241–7. [PubMed:
15240598]
110. Richman RA, Kirsch LR. Testosterone treatment in adolescent boys with constitutional delay in
growth and development. N Engl J Med. 1988; 319(24):1563–7. [PubMed: 3200264]
111. Soliman AT, Khadir MM, Asfour M. Testosterone treatment in adolescent boys with
constitutional delay of growth and development. Metabolism. 1995; 44(8):1013–5. [PubMed:
7637642]
112. Arslanian S, Suprasongsin C. Testosterone treatment in adolescents with delayed puberty:
changes in body composition, protein, fat, and glucose metabolism. J Clin Endocrinol Metab.
1997; 82(10):3213–20. [PubMed: 9329341]
113. Rogol AD. Pubertal androgen therapy in boys. Pediatr Endocrinol Rev. 2005; 2(3):383–90.
[PubMed: 16429115]
114. Kassmann K, Rappaport R, Broyer M. The short-term effect of testosterone on growth in boys on
hemodialysis. Clin Nephrol. 1992; 37(3):148–54. [PubMed: 1563120]
115. Mayo A, Macintyre H, Wallace AM, et al. Transdermal testosterone application:
pharmacokinetics and effects on pubertal status, short-term growth, and bone turnover. J Clin
116. Eiholzer U, Grieser J, Schlumpf M, et al. Clinical effects of treatment for hypogonadism in male
adolescents with Prader-Labhart-Willi syndrome. Horm Res. 2007; 68(4):178–84. [PubMed:
17374959]
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Molecular genetic causes of hypogonadotropic hypogonadism
Gene Product Inheritance Target Sites Additional Clinical Manifestations

SF-1 Orphan nuclear receptor Autosomal recessive Steroidogenesis in males XY sex reversal, adrenal failure
Hypothalamus In females: adrenal failure, normal ovarian function
Pituitary
Adrenals
Viswanathan and Eugster
DAX-1 Orphan nuclear receptor X-linked recessive Steroidogenesis In males: spectrum of hypogonadotropic hypogonadism and adrenal insufficiency
Hypothalamus
Pituitary
Adrenals
KAL-1 Anosmin X-linked recessive Hypothalamic neuronal migration Anosmia
FGFR1 FGF receptor Autosomal dominant FGF receptor in hypothalamus Cleft palate
Pituitary Agenesis of corpus callosum
GPR54 G protein coupled receptor Autosomal recessive GnRH-secreting neurons Isolated hypogonadotropic hypogonadism
Pituitary
Prop-1 Transcription factor Sporadic autosomal recessive Pituitary gonadotrope development Growth hormone deficiency
Central hypothyroidism
Hesx1 Transcription factor Sporadic Prop-1 Septo-optic dysplasia
Pituitary gonadotrope development Central hypothyroidism
Central hypocortisolism
Diabetes insipidus
LEP Leptin Autosomal dominant Hypothalamus Obesity
Hyperphagia
T-cell immune dysfunction
LEPR Leptin receptor Autosomal dominant Hypothalamus Obesity
Hyperphagia
T-cell immune dysfunction
Page 19
Table 2
Causes and clinical manifestations of congenital hypergonadotropic hypogonadism

Abnormality Clinical Manifestations

Turner syndrome Short stature, webbed neck, cubitus valgus
Streak ovaries
Klinefelter syndrome Tall stature

Eunuchoid body habitus
Small, firm testes
X chromosome abnormality Xq-premature ovarian failure

XXX-tall stature
GU abnormalities
FSH and LH β subunit mutations Males Females

Delayed puberty Primary amenorrhea
Azospermia Menstrual irregularity
Infertility Polycystic ovary syndrome
FSH and LH receptor mutations Males Females

Micropenis Primary amenorrhea
Ambiguous genitalia Gonadal dysgenesis
XY sex reversal
Infertility
Swyer syndrome (46, XY) Tall stature

Primary amenorrhea
Delayed puberty
Gonadal tumors
CAIS (46, XY) Primary amenorrhea

Normal breast development
Sparse body hair
Absent mullerian and wolffian structures
CAH (depending on deficiency) Hypertension

Hypokalemia
XY sex reversal
Adrenal crisis
Galactosemia Ovarian failure
Testicular regression sequence Normal external genitalia
Table 3
Estrogen formulations
Type of Estrogen Trade Name Available Doses

Oral estradiol Estrace 0.5, 1, 2 mg
Gynodiol 0.5, 1, 2 mg
Oral esterified estrogen Menest 0.3, 0.625, 1.25, 2.5 mg

Ogen Equivalent to 0.625 mg and above
Ortho-Est Equivalent to 0.625 mg and above
Oral conjugated equine estrogen Premarin 0.3, 0.45, 0.625, 0.9, 1.25 mg
Estradiol patches Vivelle 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d

Menostar 0.014 mg/d
Estradiol gel Divigel 0.5 mg estradiol/5 g gel

Table 4
Testosterone formulations
Formulation Trade Name Dose (Adult)

IM testosterone enanthate Delatestryl 250 mg every 2–4 wk
IM testosterone cypionate Depo-Testosterone 250 mg every 2–4 wk
Oral testosterone undecanoate Andriol (40 mg capsules) 2 capsules (2–3 times per day)
Testosterone patch Androderm 5 mg/patch changed twice weekly
Testosterone gel Androgel (25 mg testosterone/2.5 g gel) 50–100 mg/d

(50 mg testosterone/5 g gel)
Buccal testosterone Striant 30 mg tablet 1 tablet twice a day
Testosterone implants Testopel 75 mg per pellet 3–4 pellets every 4–6 mo


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Pediatr Clin North Am. 2011 October ; 58(5): 1181–x. doi:10.1016/j.pcl.2011.07.009.

Etiology and Treatment of Hypogonadism in Adolescents

In boys, hypogonadism can manifest as a complete lack of secondary sexual development or

gonadal failure is characterized as hypergonadotropic hypogonadism.

© 2011 Elsevier Inc. All rights reserved.

Constitutional Delay of Growth and Puberty

pathologic hypogonadotropic hypogonadism. In this condition, puberty and the pubertal

DAX-1 is an orphan nuclear receptor that is involved in steroidogenesis and functions as a

Isolated hypogonadotropic hypogonadism: Isolated hypogonadotropic hypogonadism

Syndromes—Numerous syndromes include neuroendocrine dysfunction as a potential

in neurologic dysfunction. TBI can have significant neurocognitive, neuropsychological, and

Hypothalamic amenorrhea—Hypothalamic amenorrhea is commonly associated with

Turner syndrome—Turner syndrome (TS) occurs in 1 in 2500 live born females.49

Klinefelter syndrome—Klinefelter syndrome is the most common congenital cause of

X chromosome abnormalities—Other X chromosome abnormalities, including Xq

phenotype similar to TS as well as isolated premature ovarian failure.55 Deletions in the

Abnormalities in gonadotropin production or action—Mutations within the β

A rare congenital condition associated with gonadotropin resistance is carbohydrate-

Disorders of sex development—Disorders of sex development (DSDs) are congenital

Swyer syndrome: Swyer syndrome, also known as XY pure gonadal dysgenesis, is

dysgerminoma or gonadoblastoma.73 Therefore, gonadectomy is routinely recommended

Complete androgen insensitivity syndrome: CAIS is caused by mutations of the androgen

Galactosemia: Another congenital cause of primary hypogonadism is galactosemia.

Testicular regression sequence: Testicular regression sequence (TRS), or vanishing testis

Chemotherapy and radiation—Both chemotherapy and radiation have been noted to

Autoimmune gonadal failure—Autoimmunity can lead to both testicular and ovarian

specifically ovary-specific antibodies, in the steroid production pathway are thought to

systemic lupus erythematous and myasthenia gravis.

can be an important clue to the presence of KS.

Physical examination should include height and weight measurements. Neurologic

Laboratory evaluation including plasma gonadotropin levels, estradiol, or testosterone may

employed to determine whether spontaneous puberty will ensue.

Limitations of oral estrogen therapy include variable bioavailability due to first-pass

throughout reproductive life.

Intramuscular, transdermal, and oral formulations of testosterone exist. The preparations

induction with alternate forms.113 Intramuscular injections of testosterone, however, can be

hypogonadism at MR imaging. Radiology. 1994; 191(1):53–7. [PubMed: 8134597]

Engl J Med. 2007; 357(9):863–73. [PubMed: 17761590]

Hum Genet. 1999; 63(Pt 3):199–206. [PubMed: 10738532]

correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab.

galactosaemia patients. Eur J Pediatr. 1997; 156(2):116–20. [PubMed: 9039515]

Molecular genetic causes of hypogonadotropic hypogonadism

Gene Product Inheritance Target Sites Additional Clinical Manifestations

Causes and clinical manifestations of congenital hypergonadotropic hypogonadism

Abnormality Clinical Manifestations

Klinefelter syndrome Tall stature

X chromosome abnormality Xq-premature ovarian failure

FSH and LH β subunit mutations Males Females

FSH and LH receptor mutations Males Females

Swyer syndrome (46, XY) Tall stature

CAIS (46, XY) Primary amenorrhea

CAH (depending on deficiency) Hypertension

Galactosemia Ovarian failure

Testicular regression sequence Normal external genitalia

Type of Estrogen Trade Name Available Doses

Oral esterified estrogen Menest 0.3, 0.625, 1.25, 2.5 mg

Estradiol patches Vivelle 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d

Estradiol gel Divigel 0.5 mg estradiol/5 g gel

Formulation Trade Name Dose (Adult)

IM testosterone cypionate Depo-Testosterone 250 mg every 2–4 wk

Testosterone patch Androderm 5 mg/patch changed twice weekly

Testosterone gel Androgel (25 mg testosterone/2.5 g gel) 50–100 mg/d